Hot-melt TTS for administering Rotigotine

ABSTRACT

This patent application relates to a transdermal therapeutic system (TTS) that comprises a Rotigotine-containing cement layer, characterized in that the cement layer contains a hot-meltable adhesive in which Rotigotine as the active substance is dispersed and partly or completely dissolved.  
     The patent application further relates to the use of Rotigotine in the production of the cement layer of a TTS by a hot-melt method.

[0001] This invention relates to a transdermal therapeutic system (TTS)encompassing a Rotigotine-containing cement matrix, characterized inthat the cement matrix contains a hot-meltable adhesive in which theactive substance Rotigotine((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-napththol)is dispersed and partly or completely dissolved.

[0002] The invention further relates to a method for producing a TTSthat encompasses a cement matrix containing Rotigotine as the activesubstance, characterized in that, prior to the coating and laminating,the components of the cement matrix are melted and homogenized, withoutany solvent, at temperatures between 70 and 200° C. and preferablybetween 120 and 160° C.

[0003] Finally, this patent application relates to the use of Rotigotinefor producing the cement matrix of a TTS by the hot-melting process.

[0004] Prior art has described various TTSs for the administration ofRotigotine.

[0005] WO 94-07468 discloses a system that contains as the activesubstance a salt in a diphasic matrix.

[0006] That diphasic matrix consists of a hydrophobic polymer in which asilicate is dispersed to accept the hydrophilic medicinal salt, assistedby the additional use of organic solvents. The matrix is produced bydrying the dispersion at 70° C. The Rotigotine content in the matrix is2-5% by weight.

[0007] That system, however, has a number of drawbacks:

[0008] (1) Its production is a multi-stage, complex process. The activesubstance must be dissolved in water or in an aqueous solvent mixture,then mixed with the silicate, then mixed with an emulsifier so as tofinally emulsify the aqueous solution with the polymer such as asilicone cement dissolved in an organic solvent, typically heptane,ethyl acetate or toluene. The resulting emulsion is difficult tomanipulate.

[0009] (2) Organic solvents are used which, during the TTS production,have to be completely removed again so as to ensure an adequate shelflife as well as reproducible release characteristics of the TTS whilepreventing skin irritations. That increases the production cost. Up tothe point where the cement contains the active substance, it is adiscontinuous process.

[0010] (3) Handling organic solvents requires stepped-up safetyprecautions to prevent any environmental impact or exposure of thepersonnel involved in the TTS production. Solvent recovery/separationequipment, measures for personnel protection and the disposal ofsolvents are all costly.

[0011] (4) On the one hand, the admixture of the active substance islimited by the degree of solubility of the Rotigotine in the solventconcerned. On the other hand, as the solvent is removed during theproduction process, the relative concentration of the active substanceincreases, which can lead to an oversaturation of the matrix and to anundesirable formation of crystals. This again places a limit on themaximum amount of the active substance that can be worked into thematrix. Yet a low-level infusion of the active substance limits therelease capacity of the matrix per unit of time and/or its functionallifespan due to a premature depletion of the active substance.

[0012] (5) The thickness of the matrix that can be obtained in oneproduction step is limited to about 100 μm (equaling about 100 g/m²) ifit is to ensure the complete removal, in the drying process, of thesolvent needed for its production. If cement matrices with a thicknessgreater than about 100 μm are required, they must be built up layer bylayer, which is a complex and cost-increasing operation.

[0013] (6) The silicate or silicone oxide remaining in the adhesivepatch constitutes a diffusion barrier for the active substance and maynegatively affect the release of the latter. It also affects the waterabsorption of the adhesive patch. The formation of pores by the removalof water-soluble matrix components at the interface with the skin canlead to an insufficiently controllable release of the active substance.

[0014] WO 99/49852 describes a TTS with Rotigotine in its free-base formcontaining an acrylate- or silicone-based adhesive system. For producingeither system, solvents are again used that will later have to beremoved again, involving the same drawbacks and limitations describedunder (2) to (5) above.

[0015] In terms of the infusion and release of Rotigotine, the twomatrices described in WO 99/49852 have these additional shortcomings:

[0016] Silicone matrices: Assuming an emulsion or solution containing anactive substance, the matrix can accept Rotigotine at about 15% byweight. In other words, there are limits to the admixability of activesubstances in silicone matrices. Increasing the Rotigotine admixture forinstance in the production of multi-day patches is possible only byadding more matrix layers, which, however, requires several proceduralsteps that make the production more complex and expensive.

[0017] Acrylate matrices: By means of solvent coating, acrylate matricescan accept Rotigotine at up to about 40% by weight. However, the higherabsorption capacity of these matrices for Rotigotine is offset by areduced capacity to release it onto the skin due to anagent-distribution coefficient that is inferior to that of siliconesystems. Obtaining adequate Rotigotine plasma levels from these systemsrequires very high charge rates. Yet relatively large amounts of theactive substance remain in the patch after its use, increasing theeffective cost of these systems while being undesirable from theperspective of drug safety.

[0018] It is therefore the objective of this invention to provide a TTSthat avoids the drawbacks and limitations associated with the use ofsolvents. In particular, the Rotigotine TTS should offer the highestpossible degree of flexibility in admixing Rotigotine even in largeramounts while releasing the Rotigotine in therapeutically effectivequantities.

[0019] The problems described above have been solved by providing, asthe first of its kind, a TTS with a Rotigotine-containing cement matrix,characterized in that the cement matrix is produced in a hot-meltingprocess, whereby the cement matrix contains a hot-meltable adhesive inwhich Rotigotine as the active substance((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-napththol)is dispersed and partly or completely dissolved.

ILLUSTRATIONS

[0020]FIGS. 1a and b show comparisons of Rotigotine permeation throughmurine skin (HMS), between a hot-melt silicone TTS and a solvent-basedsilicone TTS. FIG. 1a illustrates the release from either TTS each witha Rotigotine content of 9% by weight. FIG. 1b shows the effect of ahigher Rotigotine charge on the Rotigotine permeation from the hot-meltTTS through the murine skin.

[0021]FIG. 2 shows the effect of the wax content on the permeationthrough murine skin of Rotigotine from the hot-melt silicone TTS with aconstant 9 weight-% charge of the active substance.

[0022]FIGS. 3a and b show the effect of the Rotigotine charge on theRotigotine permeation through murine skin from the silicone-basedhot-melt TTS in the presence of 15% wax (3 a) and, respectively, 5% wax(3 b).

[0023]FIG. 4 illustrates the effect of the matrix weight on theRotigotine permeation through murine skin from a silicone-based hot-meltTTS.

[0024]FIGS. 5a and b show the effect of the content of theinternal-phase component on the cumulative (5 a) and linear (5 b)permeation of Rotigotine from the hot-melt TTS through murine skin.

[0025]FIG. 6a shows the cumulative 72-hour permeation of Rotigotine froma hot-melt silicone TTS through human skin in comparison with that froma solvent-based silicone TTS. FIG. 6b shows the cumulative 7-daypermeation of Rotigotine from a hot-melt silicone TTS through humanskin.

[0026]FIG. 7 shows the cumulative Rotigotine permeation, from hot-meltTTS with different hot-meltable cements, through murine skin.

[0027]FIG. 8 shows the cumulative permeation, through murine skin, ofRotigotine from silicone-based hot-melt TTS produced in an extruder withdifferent internal-phase components and a Rotigotine content of 9%.

[0028]FIG. 9 shows the cumulative permeation, through murine skin, ofRotigotine from EVA-based hot-melt TTS produced in the extruder withdifferent Rotigotine concentrations.

[0029]FIG. 10 illustrates an example of a TTS structure with an activesubstance-containing cement matrix (1), a backing (2) that is inert tothe constituent components of the cement matrix, and a protective film(3) that must be removed before use.

DESCRIPTION OF THE INVENTION

[0030] It was surprising to find that Rotigotine lends itself superblyto processing by the hot-melt method, that it remains stable undershort-term heating to temperatures up to at least 160° C., that it canbe homogeneously worked into matrices produced by the hot-melt process,and that it is released from the hot-melt matrices in continuous fashionand at a therapeutically desirable rate.

[0031] In particular, the inventors were surprised to find that theRotigotine, being susceptible to oxidation, remains stable in thehot-melt process even when heated to temperatures around 160° C. Whileat higher temperatures in an oxygen-containing atmosphere, Rotigotinetends to decompose in oxidative fashion, it is amazingly stable in thehot adhesive melt and is present in the matrix at a purity level that isroutinely better than 98% and generally over 99% (measured at 220 nm and272 nm per HPLC; see tables 2, 3 and 4).

[0032] The preferred method is to introduce the Rotigotine in its solidform into the homogenized matrix melt, i.e. the Rotigotine is not melteduntil it is in the hot matrix. Following brief homogenization theRotigotine-containing cement matrix is cooled again so that, in general,the Rotigotine is exposed to thermal stress for less than 5 minutes andpreferably less than 4, 3 or even 1 minute(s). The Rotigotine will thenbe present in the solidified melt. During that process the Rotigotine islargely protected from critical environmental factors (light, oxygen).

[0033] The TTSs thus produced by the hot-melt method accept a highRotigotine charge of up to 40% by weight relative to the weight of thematrix.

[0034] Overall, the TTSs produced according to this invention by thehot-melt method offer a number of advantages over prior-artsolvent-based TTSs:

[0035] Since the Rotigotine can be directly inserted in the adhesivemelt, it eliminates the solvent-related problems when higheractive-substance concentrations are used. Consequently, substantiallyhigher Rotigotine concentrations (up to over 40 weight %) can beintroduced in the TTS, in simple fashion, than would be possible in asolvent- and silicone-based process where Rotigotine concentrations ofmore than about 15 weight % can no longer be worked in as a solution. Itis thus possible to introduce surprisingly large Rotigotine amounts evenin relatively thin matrices, and in only one procedural step.

[0036] The thickness of the layer can be varied over a wide range. Forexample, matrices having a weight of more than 100 g/m² and even morethan 200 g/m² can be produced in a single step without difficulty. Itfollows that, in combination with the higher Rotigotine concentration, aRotigotine content in the TTS matrix of up to 8 mg/cm² or even more isattainable. In contrast to that, it is not possible in a single-stepoperation to introduce a Rotigotine charge of more than about 1.5 mg/cm²in a silicone TTS produced by the solvent-based process.

[0037] The use, removal, recovery or disposal by incineration of organicsolvents and the associated need for safety precautions in TTSproduction are eliminated.

[0038] Hot-melt technology permits the continuous production of the TTSmatrix from the weighing of its individual components all the way tolamination. That type of production cycle essentially offers thefollowing advantages:

[0039] Processing times are substantially reduced

[0040] The charge volume is determined via the operating time of theproduction facility. This avoids having to switch over to largerfacilities with the associated scale-up problems and/or additionalvalidation requirements.

[0041] GMP-compliant production is possible using compact equipment witha small footprint.

[0042] Using a suitable softener such as wax or the optionalincorporation of an internal phase permits delayed release of theRotigotine from the cement matrix. An appropriate TTS configurationmakes it possible to produce TTSs that release Rotigotine over a span ofseveral days, for instance 5, 6 or 7 days, in continuous fashion andtherapeutically effective quantities.

[0043] Therefore, one object of this invention is a transdermaltherapeutic system (TTS) that encompasses a Rotigotine-containing cementmatrix, characterized in that the cement matrix contains a hot-meltableadhesive in which the active substance, Rotigotine((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-napththol),is dispersed and partly or completely dissolved.

[0044] Another object of this invention is a TTS with aRotigotine-containing cement matrix produced by the hot-melt methodemploying a process in which the Rotigotine is introduced, in molten orpreferably in its solid form, into the 70-200° C. melt of thesolvent-free cement matrix. The Rotigotine is introduced in asolvent-free melt that is preferably heated to 100-170° C., desirably to120-160° C. and ideally to 130-150° C., and then processed and cooledwithin 5 minutes, preferably within 3 minutes and ideally within amaximum of 1 minute after the admixture of the Rotigotine.

[0045] The term “transdermal therapeutic system” refers to apharmaceutical formulation or device that lends itself to thetransdermal administration of an active substance through the skin of amammal, especially through the human skin, in therapeutically effectivequantities.

[0046] The term “hot-melt process” refers to a method that employsthermal energy for melting the hot-meltable adhesive and the optionallyprovided internal phase, thus obviating the need for solvents in theproduction of the cement matrix. By “hot-melt process” this patentapplication also subsumes a procedural variation involving work attemperatures below the melting point of Rotigotine, whereby the adhesivemelt contains the Rotigotine in its solid form.

[0047] The term “solvent-free” as used in this patent applicationindicates that in producing the cement matrix no solvents are used thatwould have to be removed again in the course of the production process.

[0048] The term “hot-meltable adhesive” refers to an adhesive which,when applied to the skin, is pressure-sensitive and which can beprocessed by the hot-melt method at process temperatures of 70° C. to200° C., preferably 100° C. to 170° C., desirably 120° C. to 160° C. andideally at temperatures between 130° C. and 150° C. The “hot-meltableadhesive” may consist of an adhesive or a mixture of different adhesivesthat are individually hot-meltable. Alternatively, the “hot-meltableadhesive” may be a mixture composed of an adhesive and a suitablesoftener.

[0049] These hot-meltable adhesives preferably have a dynamic viscositywhich at 160° C. and especially at temperatures between 130° C. and 150°C. is at the most 150 Pa, preferably not more than 120 Pa, desirablyless than 100 Pa and ideally less than 80 or even 60 Pa.

[0050] Examples of adhesives that are not hot-meltable per se includethe commercially available silicone adhesives. At the aforementionedprocessing temperatures, silicone adhesives would be too viscous, havinga dynamic viscosity of more than 150 Pa.

[0051] Existing patent literature discusses a variety of methods formaking highly viscous silicone adhesives hot-meltable by admixingsuitable additives (softeners). Examples of such softeners for siliconesinclude glycerol monolaurate or lauryl acetate as described in EP 835136, waxes along the formula R—C(O)—OR′ as described in EP 360 467,alkylmethyl siloxane waxes as described in EP 524 775, siloxatedpolyether waxes as described in EP 663 431, or organic waxes asdescribed in US RE 36 754.

[0052] The softeners are usually added to the silicone adhesive inquantities from 1-30 weight % relative to the overall hot-meltablecement mixture. The preferred softeners are organic waxes as describedin US RE 36 754, such as ozokerite, ceresine, paraffin, candelilla,carnauba, bee's wax or mixtures of these waxes, with ozokerite andceresine being particularly preferred.

[0053] Ready-mixed hot-meltable silicone adhesives, especially mixturesof silicone adhesives and ceresine or ozokerite, are available from DowCorning in Michigan. Adding for instance 10 weight % of ceresine to asilicone adhesive succeeded in reducing the dynamic viscosity of theresulting adhesive mixture, at a processing temperature of 160° C., fromover 150 Pa to below 50 Pa. That type of silicone-based adhesive mixturelends itself well to being processed by the hot-melt method within atemperature range from 100° C. to 200° C. and especially in the rangebetween 120° C. and 160° C.

[0054] A surprising discovery showed that hot-meltable siliconeadhesives are superbly suitable for the transdermal administration ofRotigotine.

[0055] Therefore, one object of this invention is a transdermaltherapeutic system (TTS) that encompasses a Rotigotine-containing cementmatrix, characterized in that the cement matrix contains a hot-meltableadhesive in which the active substance, Rotigotine((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-napththol),is dispersed and partly or completely dissolved, said hot-meltableadhesive containing a suitable mixture of a silicone-based adhesive andat least one softener.

[0056] Another aspect of this invention consists of a TTS thatencompasses a cement matrix containing:

[0057] (a) 50-99 weight % of an adhesive mixture composed of

[0058] (i) 70-99 weight % of an amine-resistant silicone adhesive

[0059] (ii) 1-30 weight % of a suitable softener

[0060] (b) 1-40 weight % Rotigotine

[0061] In a preferred implementation of the invention, the saidsilicone-based hot-meltable adhesive consists of

[0062] (a) 70-99 weight % of an amine-resistant silicone adhesive and

[0063] (b) 1-30 weight %, preferably 3-15 weight % and most desirably4-10 weight % of an organic wax ideally selected from the groupencompassing ozokerite, ceresine, paraffin, candelilla, carnauba, bee'swax or mixtures of these waxes, with particular preference given toozokerite and especially ceresine.

[0064] As shown in FIG. 1a, a silicone-based hot-melt TTS of this simplecomposition produces in-vitro Rotigotine permeation rates comparable tothose of prior-art, therapeutically effective, solvent-based siliconeTTSs.

[0065]FIG. 1b shows that, with an appropriately high infusion of thehot-melt silicone TTS per this invention, in-vitro flux rates can beachieved that are clearly above the rates attainable with prior-art,clinically effective, solvent-based silicone patches.

[0066] For the purpose of this patent application the term “hot-meltTTS” refers to a TTS whose cement matrix was produced by the hot-meltmethod, meaning by the solvent-free melting of the hot-meltable adhesiveand, where applicable, additional components.

[0067] A surprising discovery showed that adding wax, especially organicwax such as ceresine or ozokerite, also has an effect on the in-vitromurine-skin permeation of Rotigotine from the hot-melt silicone TTS. Asis evident from FIG. 2, Rotigotine's permeation rate decreases as thewax concentration increases. This can be explained by a partialRotigotine distribution in the wax and a concomitant retardation effect.

[0068] This property of the wax is significant especially for developinga TTS designed for application over several days, for instance 7 days.That type of multi-day patch requires a high infusion of Rotigotine,which poses the risk of an excessive release of Rotigotine at thebeginning of the application phase (“dose dumping”). It is thereforedesirable to work into the TTS a component that controls the release ofthe active substance. This could be in the form of a membrane attachedto the bottom of the matrix for controlling the release of the activesubstance. However, such a membrane increases material cost and makesthe TTS structure more complex. It would therefore be desirable, insteadof adding such a membrane, to include suitable retardant components inthe matrix.

[0069] Apart from the surprising discovery that the wax content in thematrix serves to retard the release of the active substance, varying thewax content will not only modify the dynamic viscosity of the adhesivebut additionally offers the equally surprising option of regulating theactive-substance release.

[0070] As the wax content increases, the dynamic viscosity of thesilicone adhesive initially drops off sharply to where the wax contentis about 5 weight %, after which it decreases only slightly. Thus, whenthe wax content is 4-10 weight %, the dynamic viscosity of the siliconeadhesive is at a level that suitably permits hot-melt processing whileat the same time its effect on the Rotigotine release is minor. Higherwax concentrations will additionally produce a retardation effect.

[0071] Similarly, the effect of the wax on the rheological properties ofthe TTS is surprising. If an organic wax is used as the softener for asilicone adhesive, the dynamic viscosity of the adhesive mixturedecreases at elevated temperatures, which in excellent fashion permitsthe processing of the silicone-based cement mixture by the hot-meltmethod. At the same time, the rheological properties of the silicone,such as its cohesivity, unexpectedly remain fairly unaffected at roomtemperature, so that the typical problems with hot-meltable adhesivessuch as cold flux on the patient's skin are not encountered.

[0072] Suitable silicones include all of the silicone adhesives employedin adhesive-patch technology. The preferred silicone adhesives areamine-resistant, pressure-sensitive polyorganosiloxane adhesives.

[0073] In most cases, the silicone adhesives are polydimethyl siloxanes,but in principle it is just as possible to use in place of the methylgroups other organic radicals such as ethyl or phenyl groups.

[0074] Amine-resistant silicone adhesives generally offer the advantagethat they contain no or only few free silanol functions since theirSi—OH groups were alkylated. That type of adhesives has been describedin EP 180 377. The particularly preferred adhesive cements includecondensates or mixtures of silicone resins and polyorganosiloxanes asdescribed for instance in US RE 35 474.

[0075] These silicone adhesives are commercially available and aremarketed for instance by Dow Corning as Bio-PSA Q7-4300 or Bio-PSAQ7-4200. Also available from Dow Corning are hot-meltable siliconeadhesives that are mixtures of PSA 7-4300 with organic waxes such asozokerite or ceresine.

[0076] The active substance, Rotigotine, may be present atconcentrations of 1 to more than 40 weight % relative to the weight ofthe total cement layer, either as a salt or in free-base form.Preferably, the cement matrix contains the Rotigotine in free-base form.

[0077] Unlike the solvent-based silicone adhesives whoseactive-substance content is 15 weight % at the most, the adhesivematrices of hot-melt TTSs can accept significantly greater amounts ofRotigotine without requiring any additional technical measures. Thatagain provides greater flexibility in selecting the permeation rate andthe release period of the hot-melt TTS.

[0078] As is evident from the example of a silicone-based hot-melt TTSin FIGS. 3a and 3 b, a higher Rotigotine charge allows for a higher fluxrate through mammalian skin as well as a longer Rotigotine release time.In applying a TTS on human skin, the particular effect of a higherRotigotine concentration is an extended Rotigotine release while from an8-9% Rotigotine concentration on up the permeation rate through humanskin increases only marginally.

[0079] The preferred Rotigotine concentrations in the adhesive layer are440 weight %, especially 9-30 weight % and more specifically 9-25 weight% or 15-25 weight %, for 7-day patches they are 20-40 weight % andespecially 25-35 weight %, relative to the total weight of the adhesivelayer.

[0080] Varying the layer thickness of the cement matrix serves as anadditional element in controlling the Rotigotine release rate andduration. The example of a hot-melt silicone TTS in FIG. 4 shows theeffect of the weight of the matrix on the in-vitro permeation ofRotigotine through murine skin.

[0081] The thickness of the cement matrix can be flexibly selected overa wide range and in one single procedural step, since the layerthickness is not subject to the limitations associated with thesolvent-based method. The layer thickness may be between 30 and 300 μm,preferably between 50 and 150 μm and most desirably between 50 and 120μm.

[0082] The weight of the cement matrix of the TTS according to thisinvention is preferably between 30 and 300 g/m², desirably between 50and 150 g/m² and ideally between 50 and 120 g/m²; for 7-day patches itis preferably 70-200 g/m², desirably 80-180 g/m² and ideally 100-160g/m².

[0083] The preferred Rotigotine content in the matrix is between 0.4mg/cm² and 8 mg/cm², depending on for how long the TTS is to be applied.

[0084] For a 1-day TTS the preferred concentration is between 0.4 and1.5 mg/cm² and most desirably between 0.4 and 0.8 mg/cm².

[0085] The average therapeutically required dose is about 6 mg ofRotigotine per day. Hence, a 7-day patch requires about 42 mg of theactive substance per TTS. For safety considerations, clinically employedtransdermal systems are assumed to draw only about 50-60% of the TTSsupply, which is why a 7-day TTS should contain at least 70 to 80 mg ofthe active substance.

[0086] Consequently, given a 7-day-patch TTS size of preferably 10-30cm² and most desirably 15-25 cm², the preferred Rotigotine charge willbe as follows: Patch Size Minimum Rotigotine in cm² Content in mg/cm² 107.0-8.4 15 4.7-5.6 20 3.5-4.2 25 2.8-3.4 30 2.3-2.8

[0087] Accordingly, the preferred Rotigotine content in 7-day patches isbetween about 2 mg/cm² and 8 mg/cm², desirably between about 2.8 mg/cm²and 5.6 mg/cm² and ideally between 3.1 and 5.6 mg/cm².

[0088] So far, prior art has not disclosed any TTS for theadministration of Rotigotine in therapeutically significant quantitiesat this high level, which at this point is possible only by the variablecharging and layer thickness of the hot-melt TTS. The high Rotigotineconcentration of up to over 40 weight % makes it possible even for a7-day TTS containing an appropriately large amount of Rotigotine toproduce relatively thin matrices with a layer thickness of 80-200 μm,preferably 80-180 μm and ideally 80-160 μm.

[0089] Another object of this invention therefore includes TTSs for theadministration of Rotigotine in therapeutically effective quantities,characterized in that they feature a Rotigotine concentration in thecement matrix of at least 2.0 mg/cm², preferably at least 2.8 mg/cm² andmost desirably at least 3.1 mg/cm² or at least 3.4 mg/cm². Preferred areTTSs containing matrices with a Rotigotine change rate of over 20 weight% and a matrix weight of under 200 g/m², for instance a weight ofbetween 80 and 180 g/m² and most desirably between 80 and 160 g/m².

[0090] As an option, the cement layer (also referred to as the cementmatrix) may contain, in addition to the Rotigotine and the adhesivemixture, a component that serves as the internal phase.

[0091] In particular, the internal-phase component serves as asolubilizer and crystallization inhibitor while contributing to auniform distribution of the active substance in the cement matrix. Theinternal-phase component also helps augment moisture absorption of thepatch on the skin.

[0092] For use in the hot-melt process, the most suitable internal-phasecomponents are those exhibiting at temperatures below 170° C. a dynamicmelting viscosity of not more than 150 Pa, preferably less than 120 Paand most desirably less than 80 Pa.

[0093] If at the desired processing temperature the dynamic viscosity ofthe internal-phase component is too low, a suitable softener such asglycerin may first have to be added. In some cases the active substance,Rotigotine, may itself have softening properties. This is the case forinstance with polyvinyl pyrrolidone so that, when PVP is to be meteredinto an extruder, a PVP/Rotigotine premelt can be produced.

[0094] The internal-phase components are preferably selected out of thegroup of

[0095] (a) hydrophilic or amphiphilic polymers,

[0096] (b) hydrophilic or amphiphilic copolymers,

[0097] (c) mixtures of (a) and/or (b) with pharmaceutically acceptablesofteners,

[0098] (d) condensates from glycerin with fatty acids or polyols,

[0099] (e) suitable mixtures of the substances (a)-(d).

[0100] Internal-phase components suitable for use in the TTS per thisinvention may be selected for instance from the group ofpolysaccharides, substituted polysaccharides, polyethylene oxides,polyvinyl acetates, polyvinyl pyrrolidones (PVP), PVPs with suitablesofteners, polyethylene glycols, polypropylene glycols, acrylates,copolymers from polyvinyl pyrrolidone and (poly)vinyl acetate,copolymers from ethylene and vinyl acetate, as well as polyvinylalcohols with a suitable softener such as glycerin.

[0101] The preferred internal-phase components are PVP, PVP withsoftener, polyethylene oxides (PEO), polyvinyl acetates (PVA), andcopolymers from PVP and vinyl acetate.

[0102] The internal-phase component is added to the cement layer at aconcentration of 0-40 weight % as related to the overall weight of thecement layer, with the preferred amount of the added internal-phasecomponent being 2-25 weight %.

[0103] A surprising discovery was made whereby, given a constant amountof the active substance and perhaps a softener, the internal-phasecomponent not only promotes the solubility of the Rotigotine and thusits uniform distribution in the matrix but, as the quantity isincreased, it also leads to a retardation i.e. linearization of theRotigotine release.

[0104] Using the example of a silicone-based hot-melt TTS, FIGS. 5a and5 b show the effect of the PVP content on the in-vitro Rotigotinepermeation through murine skin. As the PVP content is increased, itleads to a linearization of the Rotigotine permeation rate (FIG. 5a)that is attributable to a significant reduction of the initial releaseof the active substance (FIG. 5b).

[0105] This retardation effect of the internal-phase component can beutilized for instance in the case of hot-melt TTSs with a highactive-substance charge for producing a patch that releases the activesubstance, Rotigotine, in uniform, therapeutically effective quantitiesover an extended period such as at least 3 days, or at least 4, 5, 6 or7 days.

[0106] Assuming an average daily dose of 6 mg Rotigotine, the necessaryhourly steady-state Rotigotine flux rate will be 250 μg. For a TTS witha surface area of between 10 and 30 cm² that means a necessary flux rateof 8.3-25 μg/cm²/h.

[0107] In in-vitro permeation experiments on human skin with thedisclosed silicone-based hot-melt TTS having a Rotigotine charge ofabout 23-25 weight % and a patch weight of 54-84 g/m², i.e. a Rotigotinecontent of 1.2-2.1 mg/cm² of matrix, it was possible to achievecontinuous flux rates of 12-16 μg/cm²/h over a period of at least 3 days(see FIG. 6a).

[0108] That flux rate was on the order of magnitude of the clinicallyrelevant flux rate obtained with the comparative silicone-based TTSproduced by the solvent method. After about 48 hours, with theactive-substance supply exhausted, the permeation curve of thecomparative TTS broke off while the supply of the more highly chargedhot-melt TTS was not exhausted even after 72 hours.

[0109] Applying the hot-melt TTS according to this invention on a humanskin model as described in Implementation Example #9, a Rotigotineconcentration of 25 weight % and a matrix weight of 85 μm² made itpossible, after an initial lag phase, to maintain a 7-day steady-stateflux rate through the human skin of about 15 μg/cm²/h (FIG. 6b).

[0110] Therefore, one object of this invention is a TTS whose cementmatrix contains Rotigotine as the active substance in an amount of atleast 20 weight %, and preferably over 25 weight %, and which, in anin-vitro permeation test on human skin as described in ImplementationExample #9, leads to a continuous flux rate of at least 8 μg/cm²/h, orpreferably 10 μg/cm²/h, lasting over a period of at least 5, 6 or 7days.

[0111] Another object of this invention is a hot-melt TTS that containsRotigotine as the active substance in its adhesive layer in an amount ofat least 20 weight % and preferably at least 25 weight % and which, inan in-vitro permeation test on human skin as described in ImplementationExample #9, attains a continuous flux rate of at least 8 μg/cm²/h for aperiod of at least 7 days.

[0112] For standardizing the solvent-based, Rotigotine-containingsilicone TTS, the in-vitro model per Tanojo (J Contr. Release 45 (1997)41-47), used for measuring the flux rate through the human skin, hasproved to be a good model for predicting the in-vivo flux ratedetermined in clinical studies. In contrast to a few other in-vitrohuman-skin models employed for comparison purposes, the flux ratesthrough the human skin as determined by the Tanojo model correlatedexcellently with the results obtained in clinical studies (Phase III) interms of flux rates, plasma levels and clinical parameters such as theUPDRS score.

[0113] The results obtained with the model described in ImplementationExample #9 therefore suggest that the hot-melt TTS is equally suitablefor the in-vivo administration of Rotigotine in therapeuticallyeffective amounts over a period of several days.

[0114] In clinical practice, the flux is preferably set at a rate wherethe patient maintains a continuous therapeutic plasma level of between0.4 and 2 ng/mL of blood. This requires an hourly Rotigotine fluxthrough the patient's skin of 100-400 μg, preferably about 200-300 μg(corresponding to 10-15 μg/cm²/h for a 20 cm² TTS), desirably 230-270 μgand ideally about 250 μg. The standard dosage may be varied especiallyin adaptation to the patient's physical constitution. As shown in FIG.6b, this flux rate is achievable over a 7-day period employing the TTSaccording to the invention.

[0115] Thus, for the first time, a TTS for the continuous transdermaladministration of Rotigotine is provided which, when applied on humanskin, induces an average plasma concentration of 0.4-2 ng/ml Rotigotineover a period of at least 5, 6 or 7 days.

[0116] Also for the first time, a TTS is provided that is capable ofadministering Rotigotine through mammalian and especially human skin atan hourly flux rate of 200-300 μg over a period of 5, 6 or 7 days.

[0117] Therefore, one aspect of this invention is a TTS, preferably ahot-melt TTS and especially a silicone-based hot-melt TTS, that lendsitself to the continuous administration of Rotigotine over a period ofat least 5, 6 or 7 days at a steady-state flux rate of 200-300 μg/day.

[0118] Another aspect of this invention is a TTS, preferably a hot-meltTTS and especially a silicone-based hot-melt TTS, that lends itself tothe continuous administration of Rotigotine to humans over a period ofat least 5, 6 or 7 days, where over at least 80%, preferably at least90% and most desirably at least 95% of the time selected the plasmalevel in the patient's circulatory system is set at between 0.4 and 2 ngRotigotine per mL of blood.

[0119] Another object of this patent application is a TTS for thetransdermal administration of Rotigotine, encompassing anactive-substance-containing layer, characterized in that:

[0120] (a) the active-substance-containing layer

[0121] (a1) incorporates a Rotigotine component of at least 20 weight %and preferably at least 25 weight %,

[0122] (a2) has a Rotigotine concentration of at least 2.0 mg/cm²,preferably 2.8 mg/cm² and most desirably at least 3.1 mg/cm² or at least3.4 mg/cm²,

[0123] (a3) optionally contains an amount of anactive-substance-retardant organic wax and/or an internal-phasecomponent, and

[0124] (b) upon application of the TTS on the patient's skin, willtranscutaneously dispense Rotigotine over a period of at least 5 daysand preferably at least 7 days at a steady-state flux rate of 100-500μg/hour and preferably 200-300 μg/hour.

[0125] Another object of the invention is a Rotigotine-containing TTS,preferably a Rotigotine-containing hot-melt TTS and, most desirably, aRotigotine-containing silicone-based hot-melt TTS, characterized inthat:

[0126] (a) the Rotigotine is contained in the cement matrix in an amountof at least 20 weight % and preferably at least 25 weight %,

[0127] (b) the cement matrix has a Rotigotine content of at least 2.0mg/cm², preferably 2.8 mg/cm² and most desirably at least 3.1 mg/cm² orat least 3.4 mg/cm², and

[0128] (c) Rotigotine is released to the patient over a period of atleast 5, 6 or 7 days at a steady-state rate of at least 100-500 μg/hour,preferably 200-300 μg/hour and most desirably 230-270 μg/hour.

[0129] Those skilled in the art are familiar with other additives thatmay in principle be contained in the cement layer, such as antioxidants,stabilizers, tackifiers, preservatives or permeation boosters.

[0130] Whether the addition of such substances to the essentialcomponents per this invention, as defined in the claims, is useful inany given case can be determined by routine tests and suchimplementations are therefore specifically made a part of thisinvention.

[0131] In one preferred form of implementation of the invention thedisclosed hot-melt TTSs do not contain any permeation boosters.

[0132] One form of implementation of the invention is therefore ahot-melt TTS encompassing a cement matrix that contains:

[0133] (a) 50-99 weight % of a hot-meltable adhesive

[0134] (b) 1-40 weight %, preferably 5-30 weight %, desirably 9-30weight % and ideally 15-25 weight % of Rotigotine

[0135] (c) 0-40 weight %, preferably 2-25 weight % and most desirably5-25 weight % of an internal-phase component preferably selected fromamong the group of polysaccharides, substituted polysaccharides,polyethylene oxides, polyvinyl acetates, polyvinyl pyrrolidones with orwithout softeners, polyethylene glycols, polypropylene glycols,acrylates, copolymers from polyvinyl pyrrolidone and (poly)vinylacetate, copolymers from ethylene and vinyl acetate, as well aspolyvinyl alcohols with a softener such as glycerin;

[0136] (d) 0-10 weight %, preferably 0-5 weight % and most desirably0-3% of other additives such as tackifiers, antioxidants, stabilizers,permeation boosters,

[0137] where the hot-meltable adhesive (a) is preferably a mixture of

[0138] (i) 70-99 weight % of an amine-resistant silicone adhesive

[0139] (ii) 1-30 weight % of a suitable softener, especially a wax,preferably an organic wax and most desirably ozokerite or ceresine.

[0140] The hot-melt TTS may consist exclusively of the cement matrix,but in addition to the Rotigotine-containing cement matrix it preferablyincludes such components as a backing (2) that is impermeable to theactive substance and inert to the components of the cement matrix, and aprotective foil (3) that covers the cement matrix (1) and must beremoved before use (see FIG. 10). Those skilled in the art are familiarwith other possible variations of the TTS configuration, including forinstance an added membrane that controls the flux of the activesubstance, and/or an added adhesive foil (“overtape”). Particularpreference is given to the “monolithic” TTS configuration depicted inFIG. 10.

[0141] Rotigotine is a dopamine agonist. Therefore, the TTS according tothe invention is especially suitable for the treatment of diseasesassociated with dopamine-metabolic disorders, most particularlyParkinson's disease or Restless Leg.

[0142] One object of the invention, therefore, is a method for treatingdopamine-metabolic diseases, especially Parkinson's disease or RestlessLeg syndrome, characterized in that a Rotigotine-containing hot-melt TTSaccording to this invention is applied on the skin of a patient.

[0143] Another object of the invention is a product package holding oneor several Rotigotine-containing hot-melt TTSs per this invention aswell as instructions for their use.

[0144] So far, the only methods known from prior art for the productionof Rotigotine-containing TTSs have employed a solvent-basedRotigotine-containing cement matrix, requiring the removal of thesolvent from a solvent-containing silicone- or acrylate-baseddispersion. This present invention is the first to introduce asolvent-free hot-melt method for producing a Rotigotine-containing TTS.

[0145] Therefore, one aspect of this invention is a method for producinga TTS encompassing a cement matrix that contains Rotigotine as theactive substance, characterized in that, prior to being laminated onto afoil, the components of the cement matrix are melted and homogenized,solvent-free, at temperatures of between 70 and 200° C., preferablybetween 100 and 200° C. and most desirably between 120 and 160° C. Theideal operating temperature in the extruder is between 130 and 150° C.

[0146] Surprisingly, it was found that, after the melting, theRotigotine remains stable in a variety of matrices even without theaddition of stabilizers or antioxidants. HPLC measurements with UVanalyses at 220 nm and 272 nm have shown that even without the admixtureof antioxidants the purity level of the active substance routinelyremained above 98% and generally better than 99% (Table 24;Implementation Examples #4, 6, 7).

[0147] Therefore, one aspect of the invention is the use of Rotigotinein the production of a TTS, characterized in that the Rotigotine isinfused in the cement layer of the TTS by the hot-melt method.

[0148] It is entirely possible to introduce the Rotigotine in the matrixeither premelted or by metering it in solid form into the hot matrixmelt where it is melted.

[0149] In a preferred form of implementation the Rotigotine is melted attemperatures between 100 and 200° C., preferably between 120 and 160° C.and desirably between 130° C. and 150° C., in that Rotigotine in itssolid state is metered into the molten matrix, optionally without theaddition of stabilizers or antioxidants.

[0150] In a particularly preferred form of implementation the Rotigotineis melted by metering it, in its solid state, into the hot molten matrixand by briefly homogenizing and then calendering theRotigotine-containing matrix melt onto a foil substrate where it iscooled. In that operation the Rotigotine is exposed, preferably for amaximum of 5 minutes and most desirably for less than 4, 3, 2 or even 1minute(s), to a temperature of 100° C. to 200° C., preferably 120-160°C. and ideally 130-150° C.

[0151] Another aspect of this invention is, therefore, the use ofRotigotine for producing a TTS by the hot-melt method at temperatures ofbetween 120 and 160° C. and most preferably at 130° C. to 150° C.,whereby the hot-melt process produces a cement matrix containingRotigotine at a purity level of at least 98% and preferably 99% asmeasured at 220 and 272 nm.

[0152] In another form of implementation of the invention, the cementlayer of the TTS is melted at very low temperatures of 70-75° C., whichis just below the melting point of Rotigotine. That leaves theRotigotine in the matrix in its solid state. This method requires theuse of hot-meltable adhesives that permit processing at 70° C., while onthe other hand the dynamic viscosity of the adhesive mixture must not beset too low to avoid cold flux of the adhesive layer on the skin. Theprocess therefore requires the application of a fairly high shearingforce.

[0153] Therefore, one aspect of this invention is the production of aTTS by the hot-melt method, whereby the cement layer is melted attemperatures below the melting point of Rotigotine, meaning below about75° C., and the Rotigotine in its solid state is metered into the melt.

[0154] For the industrial production of the TTS the cement layer ispreferably prepared in an extruder. In that process, the individualcomponents of the cement layer can be introduced in the extruder, forinstance a dual-screw extruding machine, via the respective feedchannels either separately or in premixed form. The combined substanceis mixed in the extruder under controlled heating conditions, whereuponit can be continually processed and ultimately laminated.

[0155] Since at room temperature the hot-meltable adhesive remainssolid, premelting is necessary. That can be accomplished for instance bymeans of a melting/metering system consisting of a container withcontrolled heating, in which the hot-meltable adhesive such as thehot-meltable silicone adhesive is premelted at temperatures between 70°C. and 200° C., preferably between 100° C. and 170° C., desirablybetween 120° C. and 160° C. and ideally between 130 and 150° C. Themelting/metering system permits continuous feeding, allowing it to beeasily integrated into the continuous production system. The meteringsection may be of the volumetric or gravimetric type.

[0156] In hydrophobic adhesives such as silicones, Rotigotine is solublein trace amounts only, which is why it must be dispersed. The viscosityof the molten Rotigotine is very low, as a result of which there may beconsiderable viscosity differences during the process between theadhesive and the active substance. For optimizing the distribution ofthe active substance in the cement matrix, one has the option ofintegrating static mixing agents in the extrusion process to ensure aneven more homogeneous blending of the cement matrix. Suitable staticmixing agents are available for instance from Sulzer Chemtech GmbH. Ithas thus been possible, as verified by microscope analyses of the cementmatrix, to reduce the droplet size of the active-substance particles andof the internal-phase domains to an average of less than 20 μm.

[0157] There are several advantages to that:

[0158] For one, it prevents the formation of larger active-substanceparticles in the matrix that might lead to an uneven flux, to anadhesion/cohesion imbalance or to the recrystallization of the activesubstance.

[0159] For another, it prevents the accumulation of the active substanceat the interface between the cement matrix and the skin that could causeskin irritation and/or protonation of the active substance with theconsequent reduction of the flux rate through rediffusion of theprotonized base.

[0160] Therefore, the size of the active microparticles should notexceed 80%, preferably 60% or ideally 50% of the thickness of the cementmatrix. The average size of these microparticles is preferably in arange up to 40% and desirably up to 30% of the matrix thickness.

[0161] Assuming a matrix thickness for instance of 50 μm, the internalphase in the cement matrix would then preferably be in the form ofdroplets with an average size of up to 20 μm and preferably up to amaximum of 15 μm.

[0162]FIG. 8 shows the in-vitro permeation of Rotigotine through murineskin from different silicone-based hot-melt TTSs produced by fusedextrusion in an extruder under utilization of different internal-phasecomponents.

[0163] Apart from the silicone-based adhesive systems, otherhot-meltable adhesives are in principle equally suitable for use in theRotigotine-containing hot-melt TTSs according to this invention.

[0164] Hot-meltable adhesives have been described in prior art. Examplesof usable types include hot-meltable adhesives based on styrene blockcopolymers (“SXS adhesives”) derived from polymers with non-elastomericstyrene blocks at the ends and elastomer blocks in the middle. Theelastomer blocks may consist for instance of polyethylene butyl,polyethylene propylene, polybutadiene or polyisopropene.

[0165] Adhesives of that type have been described for instance in U.S.Pat. No. 5,559,165 and U.S. Pat. No. 5,527,536. They offer good adhesiveproperties, are easy to produce and process and are well tolerated onthe skin.

[0166] SXS adhesives can be procured commercially (e.g. as Duro Tak378-3500 from National Starch & Chemical), or they can be produced usinghot-melt extrusion equipment in the course of the production of theactive-substance-containing patches. This involves the individualmetering into and mixing and melting in the extruder of correspondingquantities (at least of the following components) of a styrene blockcopolymer (such as Shell Kraton GX1657 or Kraton D-1107CU) with a resin(such as Keyser-Mackay Regalite R1090 or Regalite R1010 or RegaliteR1100) and an oil (such as Shell Ondina 933 or Ondina 941). As the laststep, the active substance is metered into the adhesive thus produced inthe extruder and the compound is then laminated onto a foil. Examples oftypical polymer/resin/oil weight ratios are 100/120/20 or 100/200/50. Byvarying these ratios it is possible to adapt the properties of the SXSadhesive to the respectively desired properties of the TTS (adhesivestrength, minimal cold flux, adhesive duration, release pattern of theactive substance, etc.).

[0167] Because of the oxidative effect of the SXS adhesives a preferredmethod is to add antioxidants to such SXS-based cement matrices. Oneexample of a commercially available, suitable antioxidant is Irganox®(by CIBA).

[0168] Another example consists in hot-meltable adhesives that are basedon ethylene vinyl acetate copolymers (“EVA adhesives”). EVA adhesives ofthat type are described for instance in U.S. Pat. No. 4,144,317. EVAadhesives offer good adhesive properties, they are easy to produce andprocess and are well tolerated on the skin. They are available forinstance from Beardow Adams (13/BA).

[0169] It was possible both with hot-meltable SXS-type adhesives andwith hot-meltable EVA-type adhesives to produce Rotigotine-containingTTSs that encompassed hot-melt cement matrices and released theRotigotine in proper amounts (FIG. 7).

[0170]FIG. 9 shows the in-vitro permeation, through murine skin, ofRotigotine from EVA-based hot-melt TTSs with varying Rotigotinecontents, produced by fused extrusion in an extruder.

[0171] Therefore, one object of this invention is a transdermaltherapeutic system (TTS) encompassing a Rotigotine-containing cementmatrix, characterized in that the cement matrix contains a hot-meltableadhesive in which the active substance, Rotigotine,((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl)amino]-1-napththol),is dispersed and partly or completely dissolved, said hot-meltableadhesive being of the SXS-type or EVA-type.

[0172] One form of implementation of this invention is thus representedby a hot-melt TTS that comprises a cement matrix containing:

[0173] (a) 50-99 weight % of a hot-meltable adhesive,

[0174] (b) 1-40 weight %, preferably 5-30 weight %, desirably 9-30weight % and ideally 15-25 weight % Rotigotine,

[0175] (c) 040 weight %, preferably 2-25 weight % and desirably 5-25weight % of an internal-phase component preferably selected from thegroup of polysaccharides, substituted polysaccharides, polyethyleneoxides, polyvinyl acetates, polyvinyl pyrrolidones with or withoutsofteners, polyethylene glycols, polypropylene glycols, acrylates,copolymers from polyvinyl pyrrolidone and (poly)vinyl acetate,copolymers from ethylene and vinyl acetate, as well as polyvinylalcohols with a softener such as glycerin, plus 0-10 weight %,preferably 0-5% and most desirably 0-3% of other additives such astackifiers, antioxidants, stabilizers and/or permeation boosters,

[0176] with the hot-meltable adhesive per (a) preferably selected as

[0177] (a1) an EVA adhesive,

[0178] (a2) an SXS adhesive, or

[0179] (a3) a mixture consisting of

[0180] (i) 70-99 weight % of an amine-resistant silicone adhesive,

[0181] (ii) 1-30 weight %, preferably 3-15 weight % and ideally 4-10weight % of a suitable softener, preferably an organic wax—mostdesirably ceresine or ozokerite,

[0182] where, optionally, softeners may be added to the EVA adhesive(a1) and to the SXS adhesive (a2) and, if an SXS adhesive is used, anantioxidant is added.

[0183] If an individually hot-meltable adhesive for instance of the SXStype or of the EVA type is to be adapted to specific processingrequirements, it is again possible, as an option, to add othersubstances to the composition, such as softeners, tackifiers,antioxidants, amphiphilic polymers etc.

[0184] A comparison of the release pattern of Rotigotine from thevarious hot-melt adhesives revealed that the TTS with the silicone-basedhot-melt adhesive is the most efficacious. With the SXS-based andEVA-based hot-melt TTS, the Rotigotine release drops off to a level thatis no longer therapeutically effective at a point where about 30 weight% of the Rotigotine is still present in the cement matrix. By contrast,the silicone-based hot-melt TTS allowed nearly total depletion.

[0185] Therefore, a Rotigotine-containing hot-melt TTS produced with asilicone-based hot-melt adhesive as described above is given particularpreference.

EXPERIMENTS Comparative Reference Example Solvent-based Silicone TTS

[0186] 1.8 g of (free-base) Rotigotine was dissolved in 2.4 g ethanoland added to 0.4 g Collidone 90 F (dissolved in 1 g ethanol). Theresulting mixture was added to a 74% solution of silicone polymers (8.9g BioPSA 7-4201+8.9 g BIO-PSA 7-4301 [Dow Corning]) in heptane. Afteradding 2.65 g petroleum ether the mixture was agitated for 1 hour at 700RPM to produce a homogeneous dispersion. After lamination onto polyesterit was dried at 50° C. The final weight of the patch was 50 g/cm².

1^(st) Example Silicone-Based Hot-melt TTS with 15% Rotigotine Producedin Lab Quantities

[0187] (a) Silicone Hot-Melt Adhesive

[0188] The silicone-based hot-melt cements employed contained theBio-PSA 7-4300 silicone adhesive (Dow Corning, Michigan) mixed withozokerite or ceresine softeners at 5%, 10% or 15% of the overall weightof the adhesive mixture (purchased from Dow Corning).

[0189] (b) Producing the TTS

[0190] 8.5 g of a silicone-based adhesive mixture as described in (a)was heated to 160° C. over about 20 minutes until a homogeneous melt wasobtained. 1.5 g (free-base) Rotigotine was added and the mixture waskept at 160° C. for another 5 minutes. The mixture was then manuallyhomogenized and laminated onto a preheated foil (120° C., gap width 250μm). 5 cm² sections were then cut out.

2^(nd) Example Producing a Silicone-Based Hot-Melt TTS with an InternalPhase

[0191] This was produced as in Example #1, with 0.5 g of aninternal-phase component added together with the Rotigotine.

3^(rd) Example Producing a Silicone-Based Hot-Melt TTS in Lab Quantitieswith Varied Parameters

[0192] The TTSs were in all cases produced as in Examples # 1 and #2,while the different parameters such as the type of wax, the wax content,the concentration of the internal-phase component, the active-substancecontent and the patch density were varied as follows: TABLE 1Silicone-based Hot-melt TTS Actual Internal Theoret. Rotigotine Weightof Ceresine Ozokerite Phase Type Rotigotine Content Cement ContentContent & Content Content (n = 5) Matrix (n = 10) Lot No. [% w/w] [%w/w] [% w/w] [% w/w] [% w/w] [g/m²]

[0193] The Rotigotine content and the weight of the cement matrix weredetermined as follows: 10 patches sized 5 cm², 10 cm² or 20 cm² werepunched out and individually weighed, the weight was corrected bysubtracting the average weight of the blank foils (measured by weighingsections of the same size, i.e. 5, 10 or 20 cm², respectively).

4^(th) Example Producing SXS- or EVA-Based Hot-Melt TTS in LabQuantities

[0194] 8.5 g of the SXS hot-melt adhesive (Duro-Tak 34-4230 by NationalStarch & Chemical) or 8.5 g of the EVA hot-melt adhesive was heated at160° C. for about 20 minutes until a homogeneous melt was obtained. 1.5g or, respectively, 1.65 g of Rotigotine base was added and the mixturewas manually homogenized. The mixture was then laminated onto apreheated chill roll (120° C.). 5 cm² patches (for permeationexperiments) and 20 cm² patches (for determining the patch weight) werethen cut out. The matrix weight is shown in Table 2 below. TABLE 2Theoretical Actual Internal- Active- Active- Ad- Phase SubstanceSubstance Weight Purity % Lot he- Content Content Content (n = 10) (220nm/ No. sive [% w/w] [% w/w] [% w/w] [g/m²] 272 nm)

5^(th) Example Producing a Silicone-Based Hot-Melt TTS with 15%Rotigotine and 5% Internal Phase in an Extruder

[0195] A. Producing a Premelt of the Silicone-Adhesive Mixture

[0196] The desired amount of the silicone-adhesive mixture as describedin Example #1 was preheated to 140° C. and placed in a metering unit(Meltex GR 12-1 by Melzer). The mixture was then volumetrically meteredinto the extruder.

[0197] B. Producing the Cement Matrix by the Hot-Melt Method

[0198] A dual-screw extruder (25×24D by Dr. Collin GmbH) was used forsmall to moderate production quantities and a dual-screw extruder (ZSK25by Werner Pfleiderer, Stuttgart) was used for large productionquantities. The process conditions were 5 kg/h, with 120-140° C. heatzones. A Melzer CL200 was used for the laminating.

6^(th) Example: Producing a Silicone-Based Hot-Melt TTS in the Extruderwith Varied Parameters

[0199] The TTS was in all cases produced as described in Example #5,with the parameters varied as follows: TABLE 3 Internal Actual PhaseTheoret. Rotigotine Matrix Rotigotine Ceresine Type & Rotigotine ContentWeight Purity [%] Content Content Content (n = 5) (n = 10) (220 nm/ No.Lot No. Qu'ty Static Mixing [% w/w] [% w/w] [% w/w] [% w/w] [g/m²] 272nm)

[0200] groβ=large (volume)

[0201] klein=small (volume)

[0202] PVA=polyvinyl acetate; PEO=polyethylene oxide

[0203] PVPVA=polyvinyl pyrrolidone-vinyl acetate copolymer

7^(th) Example Producing EVA-Based Hot-Melt TTS in an Extruder

[0204] All TTSs were produced as described in Example #5, with the TTSshaving the following compositions: TABLE 4 Actual Theoretical Active-Rotigotine Internal- Active- Substance Purity Phase Substance ContentWeight [%] Lot Content Content (n = 5) (n = 10) (220 nm/ No. Qu'ty [%w/w] [% w/w] [% w/w] [g/m²] 272 nm)

[0205] klein=small (volume)

[0206] groβ=large (volume)

8^(th) Example Determining the Flux of the Active Substance in theMurine-Skin Model

[0207] For measuring the flux through murine skin, abdominal and dorsalskin about 120 to 150 μm thick was used. A punched-out TTS with asurface area of 2.55 cm² in a horizontal diffusion cell was fastened tothe keratic side of the abdominal and dorsal skin of hairless mice.Immediately thereafter the acceptor chamber of the cell was filled witha phosphate buffer solution (0.066 molar) preheated to 32° C., with a pH6.2 and bubble-free, and the release medium was thermostaticallycontrolled at 32±0.5° C.

[0208] At the time of the sampling the release medium was replaced withfresh medium thermostatically controlled at 32±0.5° C. The Rotigotinerelease was determined by HPLC as described in Example #10.

9^(th) Example Determining the Rotigotine Flux in the Human-Skin Model

[0209] The Rotigotine flux through human skin was essentially determinedas described by H. Tanojo et al in J. Control Rel. 45 (1997) 41-47.

[0210] For that purpose, human skin about 250 μm thick was harvestedfrom an abdomen. A TTS with a surface area of 2.545 cm² was applied onan identical area of the human skin, with the skin on the acceptor sideresting on a silicone membrane (diagram 1). The acceptor phase used wasPBS (0.066 molar) at pH 6.2 and a temperature of 32±0.5° C. Theexperiments were conducted with a flux of 5 mL/h over 72 hours, withsamples taken every 3 hours. At the time of the sampling the releasemedium was replaced with fresh medium thermostatically controlled at32±0.5° C. and the amount of the released Rotigotine was measured byHPLC. The flux rate Q(t) relative to the surface of the measuring cell(0.552 cm²) was determined using this formula:

Q(t)=μg/cm ²=Rotigotine concentration acceptor volume divided by 0.552cm ²

[0211] Diagram 1:

[0212] Patch, surface area=2.545 cm²

[0213] Human skin, surface area=2.545 cm², ˜250 μm

[0214] Silicone membrane, surface area=2.545 cm², 250 μm

[0215] Diffusion cell, surface area=1.131 cm²

[0216] With acceptor, area=0.552 cm²

10^(th) Example Rotigotine Analytics

[0217] (a) Analytics of the Active-Substance Release

[0218] The flux of the active substance through the skin preparationswas measured by HPLC (RPC18 LichroCART 75-4 Supersphere 60 selectcolumn) under the following conditions: 650 parts by volume (VP) water,350 VP acetonitrile, 0.5 VP methane sulfonic acid; room temperature;wavelength: 272 nm; flux 2 ml.

[0219] (b) Analytics of the Active Substance in the Matrix

[0220] (b1) Preparing the Matrix

[0221] The cement matrix was mixed with 0.1% methane sulfonic acid,agitated, centrifuged and measured.

[0222] (b2) Analytics of the Active-Substance Content

[0223] The active-substance content was determined by isocratic HPLCunder the following conditions:

[0224] Solubilizer: 65 volume parts water with 0.05% methane sulfonicacid; 35 volume parts acetonitrile with 0.05% methane sulfonic acid.

[0225] Column: LiChroCART 75×4 mm, Supersphere 60 RP-select B 5 μm

[0226] Flow rate: 2 mL/min, column temperature: 30° C.

[0227] UV detection (272 nm)

[0228] (b3) Analytics of the Active-Substance Stability:

[0229] The purity of, the Rotigotine was determining by the gradientHPLC method with an aqueous

[0230] and an organic (acetonitrile) phase, each with 0.05% methanesulfonic acid added. The organic component rose from the initial 5% to60% over 35 minutes.

[0231] Column: LiChrosphere 100 CN, 125 mm×4.6 mm, 5 μm

[0232] Flow rate: 1.0 mL, column temperature: 40° C.

[0233] UV detection (2 wavelengths, 272 and 220 nm)

[0234] (b4) Determining the Dynamic Viscosity

[0235] The dynamic viscosity was determined as described in RE 36754.

1. Transdermal therapeutic system (TTS) comprising anactive-substance-containing cement matrix, characterized in that thecement matrix contains a hot-meltable adhesive in which the activesubstance, Rotigotine((−)-5,6,7,8-tetrahydro-[propyl[2-(2-thienyl)ethyl)amino]-1-naphthol),is dispersed and partly or completely dissolved.
 2. TTS as in claim 1,for which the active-substance-containing cement matrix is produced bymetering the Rotigotine into the solvent-free melt of the cement matrixat a temperature of between 70° C. and 200° C.
 3. TTS as in claim 1 or2, in which the hot-meltable adhesive consists of a mixture of anamine-resistant silicone adhesive and at least one suitable softener. 4.TTS as in claim 3, in which the softener is an organic wax.
 5. TTS as inclaim 3 or 4, in which the softener is ceresine or ozokerite.
 6. TTS asin one of the preceding claims, in which the percentile proportion ofthe Rotigotine in the cement layer is 4-40 weight %.
 7. TTS as in one ofthe preceding claims, in which the percentile proportion of theRotigotine in the cement layer is 9-30 weight %.
 8. TTS as in one of theclaims 1-6, in which the percentile proportion of the Rotigotine in thecement layer is 20-40 weight %.
 9. TTS as in one of the precedingclaims, in which the Rotigotine is present as the biocatalytic base. 10.TTS as in one of the preceding claims, in which theactive-substance-containing cement matrix additionally contains aninternal-phase component selected from the group of (a) hydrophilic oramphiphilic polymers (b) hydrophilic or amphiphilic copolymers (c)mixtures of (a) and/or (b) with pharmaceutically acceptable softeners(d) condensates from glycerin and fatty acids or polyols (e) suitablemixtures of the components (a)-(d)
 11. TTS as in claim 10, in which theinternal-phase component is selected from the group of polysaccharides,substituted polysaccharides, polyethylene oxides, polyvinyl acetates,polyvinyl pyrrolidones, copolymers from polyvinyl pyrrolidone and(poly)vinyl acetate, polyethylene glycol, polypropylene glycol,copolymers from ethylene and vinyl acetate, glycerin-fatty acid ester aswell as mixtures of polyvinyl alcohol with glycerin.
 12. TTS as in claim1, characterized in that the cement matrix comprises (a) 50-99 weight %of a hot-meltable adhesive (b) 4-40 weight % Rotigotine (c) 0-40 weight% of an internal-phase component (d) 0-10 weight % other adjuvants 13.TTS as in claim 12, for which the hot-meltable adhesive (a) selected is(a1) an EVA adhesive (a2) an SXS adhesive, or (a3) a mixture of (i)70-99 weight % of an amine-resistant silicone adhesive (ii) 1-30 weight% of a suitable softener
 14. TTS for the continuous transdermaladministration of Rotigotine, characterized in that, for a period of atleast 5 days following its application on human skin, said TTS inducesin the patient an average plasma concentration of 0.4 to 2 ng per mlRotigotine.
 15. TTS as in claim 14, characterized in that the TTSinduces in the patient an average plasma concentration of 0.4 to 2 ng/mlRotigotine for a period of at least 7 days.
 16. TTS as in one of thepreceding claims, characterized in that the Rotigotine is transportedthrough the skin at a steady-state flux rate of 200-300 μg per hour. 17.TTS as in one of the claims 14-16, said TTS comprising aRotigotine-containing layer, characterized in that theactive-substance-containing layer (a) contains Rotigotine in apercentile proportion of at least 20 weight %, (b) has a Rotigotinecontent of at least 2.0 mg/cm², and (c) optionally contains an organicwax and/or internal-phase component in an amount sufficient to retardthe release of the active substance.
 18. Method for producing a TTS thatencompasses a cement matrix containing Rotigotine as the activesubstance, characterized in that prior to their lamination thecomponents of the cement matrix are melted and homogenized,solvent-free, at temperatures between 70° C. and 200° C.
 19. Method asin claim 18, characterized in that the components of the cement matrixare melted and homogenized in an extruder.
 20. Use of Rotigotine in theproduction of a TTS by the hot-melt method, characterized in that theRotigotine is introduced, at temperatures between 70° C. and 200° C., inthe TTS cement matrix that has been premelted without solvents. 21.Method or use as in one of the preceding claims, whereby the hot-meltingprocess takes place at temperatures between 120° C. and 160° C. 22.Method or use as in one of the preceding claims, whereby the Rotigotineis introduced, in the cement-matrix melt, in its solid state.
 23. Methodor use as in one of the preceding claims, whereby the cement matrix,produced by the hot-melting process, contains Rotigotine at a puritylevel of at least 98% as measured by HPLC at 220 nm and 272 nm.